Despite escalating efforts to identify anti-prostate cancer agents, advanced prostate cancer is still a universally progressive and fatal disease. This unusual resistance to conventional chemotherapeutic agents has led to the exploration of a variety of novel therapeutic strategies.
The prostate specific membrane antigen (PSMA) is a type II transmembrane protein found predominantly in the prostate, with minor expression of isoforms in the small intestine, brain, and tumor neovascularity (Heston, W. D (1996) Urologe A. 35:400-407). Though the precise function of PSMA is not know, it is known to be a membrane bound carboxypeptidase and folate hydrolase (Heston, W. D (1996) Urologe A. 35:400-407). This protein can exist in two forms, PSMA and PSM′. PSMA is the membrane bound form and PSM′ is an intracellular form which lacks the transmembrane domain at the amino terminus. PSM′ is the predominant form in the benign prostatic cell, while PSMA expression increases and predominates with the more aggressive prostate cancer tumor grades. Importantly, androgen suppression appears to increase PSMA expression in advanced prostate cancers. Hence, this cell surface target has been widely viewed as one of the best cell surface markers for targeted molecular therapeutics. Although there has been theoretical concern that background expression in the intestine and brain may lead to aberrent targeting with this marker, antibody based imaging and therapeutics have failed to demonstrate significant targeting to these ancillary tissues (Yao, D. et al. (2002) Semin. Urol. Oncol. 20:211-8). Hence, it appears that from a clinical point of view, PSMA has all the features necessary for consideration as a systemic target for metastatic prostate cancer. Namely, its expression increases in aggressive cancers, androgen suppression results in up regulation and background expression in other tissues does not appear to be a clinically significant source of aberrent targeting (Gong, M. C. et al. (2000) Mol. Urol. 4:217-223). Unfortunately, there exist a limited number of methodologies useful for targeting PSMA. Accordingly, there exists a need in the art for additional methods of targeting PSMA for the diagnosis and treatment of prostate cancer.